This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HIV-1 infection is associated with the loss of CD4+ T cells, chronic immune activation and progressive immune dysfunction. HIV-specific responses become impaired early after infection and play a major role in disease progression to AIDS. Immuno-modulatory therapies that restore virus specific immunity may defend against the disease progression. We used a novel humanized mouse model to study the progression of HIV-1 infection and to identify the immunotherapeutic targets in AIDS related T cell dysfunction. Human hematopoietic CD34+ stem cells transplanted into new born NOD/scid-IL-2Rgcnull immunodeficient mice develop into a functional human immune system. Reconstituted mice are susceptible to HIV-1 infection and develop realated pathology with a decline in CD4+ T cells and immune activation. Expression of co-inhibitory molecules associated with immune dysfunction, including Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), Programmed Death-1 (PD-1) and its ligands PD-L1 and PD-L2, and B and T cell attenuator (BTLA), was analyzed by flow cytometry in peripheral blood and lymphoid tissues. Chronic HIV-1 infection in mice resulted in PD-1, BTLA and CTLA4 expression on human lymphocytes, and PD ligands being upregulated on antigen presenting cells. Therapeutic approaches to augment immune responses to HIV-1 include either blocking these negative regulators of T cell function or directly targeting B cell regulators such as CD40 to regulate B cell responses. As a first attempt to modulate immune responses in HIV-1 infection we tested CD40 antibody in humanized mice to augment B cell function and restore humoral immune responses. Humanized mice are promising translational models to evaluate pre-clinical immuno-therapeutics.